US 5,932,538 AGranted

Nitrosated and nitrosylated .alpha.-adrenergic receptor antagonist compounds, compositions and their uses

AssigneeNitroMed, Inc.

InventorsDavid S. Garvey, Joseph D. Schroeder, Inigo Saenz de Tejada

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Abstract

Disclosed are nitrosated and nitrosylated .alpha.-adrenergic receptor antagonists, compositions of an .alpha.-adrenergic receptor antagonist (.alpha.-antagonist), which can optionally be substituted with at least one NO or NO.sub.2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO.sup.+) or nitroxyl (NO.sup.-), or as the neutral species, nitric oxide (NO.circle-solid.); and uses for each of them in treating human male impotence or erectile dysfunction.

Claims20

Dependent claims

A nitrosated or nitrosylated .alpha.-adrenergic receptor antagonist which is a compound having the structure:

##STR33## wherein R.sub.h is hydrogen, --C(O)--OR.sub.d or --C(O)--X wherein X is (1) --Y--(C(R.sub.e)(R.sub.f)).sub.p --G--(C(R.sub.e)(R.sub.f)).sub.p --T--Q;
wherein G is (i) a covalent bond;
(ii) --T--C(O)--;
(iii) --C(O)--T--;
or (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and that is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalky, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.m is a 3-, 4-, 5-, 6-, or 7-membered non-aromatic ring containing at least one nitrogen atom, oxygen, or sulfur atom;
Y is oxygen, sulfur, or NR.sub.i in which R.sub.i is hydrogen or lower alkyl;
R.sub.d is hydrogen, lower alkyl, or cycloalkyl, or R.sub.d is a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro, or R.sub.d is a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro;
R.sub.e and R.sub.f are independently selected from hydrogen, lower alkyl, cycloalkyl, alkylamino and dialkylamino, or R.sub.e and R.sub.f are independently selected from a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro, or R.sub.e and R.sub.f are independently selected from a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and that is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.e and R.sub.f are independently a lower alkyl appended to a mono- or bi-cyclic ring system having one or two aromatic rings that is unsubstituted or substituted with one, two or three substituents indpendently selected from lower alkyl, halo alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.e and R.sub.f taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is a covalent bond, oxygen, sulfur or nitrogen and Q is --NO or --NO.sub.2 ;
or (2) ##STR34## wherein W is a 3-, 4-, 5-, 6-, or 7-membered non-aromatic ring containing at least one nitrogen atom, oxygen, or sulfur atom, or W is NR.sub.i R'.sub.i wherein R.sub.i and R'.sub.i are independently selected from lower alkyl and alkenyl, or R.sub.i or R'.sub.i are independently selected from a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which may be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro;
and wherein R.sub.j is --D or --(O)CR.sub.d, and D is (i) --NO, (ii) --NO.sub.2 ;
(iii) --C(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p --T--Q in which R.sub.d, Y, R.sub.e, R.sub.f, p, T and Q are as defined above;
(iv) --(CO)--T.sup.1 --(C(R.sub.e)(R.sub.f)).sub.p --T.sup.2 --Q wherein T.sup.1 and T.sup.2 are independently selected from T, and R.sub.e, R.sub.f, p and T are defined above;
or (v) --C(O)--T(C(R.sub.y)(R.sub.z)).sub.p wherein R.sub.y and R.sub.z are independently selected from --T.sup.1 --(C(R.sub.e)(R.sub.f)).sub.p --G--(C(R.sub.e)(R.sub.f)).sub.p --T.sup.2 --Q wherein G, R.sub.d, R.sub.e, R.sub.f, p Q and T are as defined above.

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Dependencies are inferred from the claim text.

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Abstract

A nitrosated or nitrosylated .alpha.-adrenergic receptor antagonist which is a compound having the structure:

##STR33## wherein R.sub.h is hydrogen, --C(O)--OR.sub.d or --C(O)--X wherein X is (1) --Y--(C(R.sub.e)(R.sub.f)).sub.p --G--(C(R.sub.e)(R.sub.f)).sub.p --T--Q;
wherein G is (i) a covalent bond;
(ii) --T--C(O)--;
(iii) --C(O)--T--;
or (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and that is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalky, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.m is a 3-, 4-, 5-, 6-, or 7-membered non-aromatic ring containing at least one nitrogen atom, oxygen, or sulfur atom;
Y is oxygen, sulfur, or NR.sub.i in which R.sub.i is hydrogen or lower alkyl;
R.sub.d is hydrogen, lower alkyl, or cycloalkyl, or R.sub.d is a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro, or R.sub.d is a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro;
R.sub.e and R.sub.f are independently selected from hydrogen, lower alkyl, cycloalkyl, alkylamino and dialkylamino, or R.sub.e and R.sub.f are independently selected from a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro, or R.sub.e and R.sub.f are independently selected from a mono- or bi-cyclic ring system containing one or two aromatic rings and comprising at least one nitrogen, oxygen or sulfur atom in at least one aromatic ring, and that is unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.e and R.sub.f are independently a lower alkyl appended to a mono- or bi-cyclic ring system having one or two aromatic rings that is unsubstituted or substituted with one, two or three substituents indpendently selected from lower alkyl, halo alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro, or R.sub.e and R.sub.f taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is a covalent bond, oxygen, sulfur or nitrogen and Q is --NO or --NO.sub.2 ;
or (2) ##STR34## wherein W is a 3-, 4-, 5-, 6-, or 7-membered non-aromatic ring containing at least one nitrogen atom, oxygen, or sulfur atom, or W is NR.sub.i R'.sub.i wherein R.sub.i and R'.sub.i are independently selected from lower alkyl and alkenyl, or R.sub.i or R'.sub.i are independently selected from a mono- or bi-cyclic carbocyclic ring system having one or two aromatic rings which may be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro;
and wherein R.sub.j is --D or --(O)CR.sub.d, and D is (i) --NO, (ii) --NO.sub.2 ;
(iii) --C(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p --T--Q in which R.sub.d, Y, R.sub.e, R.sub.f, p, T and Q are as defined above;
(iv) --(CO)--T.sup.1 --(C(R.sub.e)(R.sub.f)).sub.p --T.sup.2 --Q wherein T.sup.1 and T.sup.2 are independently selected from T, and R.sub.e, R.sub.f, p and T are defined above;
or (v) --C(O)--T(C(R.sub.y)(R.sub.z)).sub.p wherein R.sub.y and R.sub.z are independently selected from --T.sup.1 --(C(R.sub.e)(R.sub.f)).sub.p --G--(C(R.sub.e)(R.sub.f)).sub.p --T.sup.2 --Q wherein G, R.sub.d, R.sub.e, R.sub.f, p Q and T are as defined above.

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